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Block 6; Week 2-Michelle > Buxton1 > Flashcards

Buxton1 Flashcards

1
Q

After a drug is given by IV admin…it disappears from the bloodstream. Where does it go first? Second Third?

A

First: brain, heart, liver & kidney
Second: skeletal muscle & skin
Third: Adipose Tissue
**think: where does blood go?

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2
Q

If someone is obese, how might this change drug delivery?

A

Some drugs might partition to fat b/c they are highly lipid soluble.

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3
Q

T/F Drugs are often weak acids or bases. This matters b/c H+ influences ionization of drugs.

A

True.

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4
Q

When drugs are unionized (in the presence of H+) what happens?

A

They are able to move across the lipid bilayer.

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5
Q

In the presence of acid, the weak base is _______. Will/Won’t allow passage across the membrane.

A

Ionized. Won’t allow passage.

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6
Q

pH<pKa: which forms dominate?

A

Protonated forms. Unionized. Move across the membrane.

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7
Q

pH>pKa: which forms dominate?

A

Deprotonated forms. Ionized. Don’t move across the membrane.

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8
Q

What is volume of distribution?

A

“The fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma.”

It is a measure of where the drug is not.

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9
Q

A “good drug” distributes how? What volume of distribution would it have roughly?

A

A good drug distributes to tissues quickly. It would have a high Vd (volume of distribution).

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10
Q

What is the equation for Volume of distribution?

A

Vd = Dose/Concentration in the blood

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11
Q

If you have a higher Vd…what does this do to your plasma conc’n at a given time & your ultimate half life?

A

Plasma conc’N: lower

Half Life: Longer.

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12
Q

What is the equation for half life?

A

T1/2 = 0.693 x Vd / Cl

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13
Q

What is the equation you can use to predict the peak amount of a drug in the blood stream?

A

Peak = Dose/Vc

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14
Q

What is the theoretical maximum Vc?

A

5.5L. The amount of blood in your bloodstream. This would be the case if the drug didn’t distribute at all.

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15
Q

What are the factors that cause a drug to stay in the central compartment?

A

Protein binding and partitioning of drug to erythrocytes retains drug in the central compartment.

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16
Q

A drug that stays in the central compartment has a high/low capacity & a high/low affinity.

A

High capacity. Low Affinity.

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17
Q

What is peripheral volume, Vt?

A

The peripheral volume is the sum of all of the spaces outside the central compartment into which the drug distributes. The peripheral volume will vary widely for disparate drugs.

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18
Q

Vt + Vc=?

A

Vt + Vc=apparent Vd.

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19
Q

Where is the sink hole for drug metabolism?

A

LIVER

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20
Q

One transporter in the liver, OATP (Organic anion-transporting polypeptide) brings in several drugs for metabolism. Name 3.

A

HMG-CoA reductase inhibitors (statins), ACE-inhibitors, and chemotherapeutics.

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21
Q

What are 3 important members of the OATP superfamily?

A

OATP1B1, OATP1B3 and OATP2B1.

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22
Q

OATP1B1 is only found in the liver. OATP2B1 is found other places. What are they?

A

brain, intestine, placenta, heart and platelets

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23
Q

OATP1B3 is found in places other than the liver. What are they?

A

placenta stomach, colon and prostate.

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24
Q

Cyclosporin inhibits a number of transporters that affect drug elimination. What are the transporters that are affected?

A

OATP2B1 & OATP1B1
CYP3A4
ABCB1 & ABCC2

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25
Q

What can inhibition of ABCB1 & ABCC2 lead to?

A

Enhanced intestinal absorption of co-administered drugs

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26
Q

Quindine & Dronedarone can both turn up exposure of the body to this drug. Rifampin can turn it down. What is the drug?

A

Digoxin

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27
Q

Probenecid turns up exposure to what drug?

A

Cephradine

28
Q

Cimetidine turns up exposure to what drug?

A

Metformin

29
Q

Cyclosporine greatly affects (increases) exposure to what drug? It does this via which 2 transporters?

A

Rosuvastatin
Via OATP & Breat Cancer Resistance Protein=ABCG2 Effflux transporter
**it also increases exposure to pitavastatin

30
Q

Lopinavir/Ritonavir increases exposure to ______ via OATP inhibition.

A

Rosuvastatin too!

31
Q

Phase 1 of drug metabolism involves what types of enzymes? Give examples.

A

Oxygenases
Cytochrome P450s (P450 or CYP)
Flavin-containing monooxygenases (FMO)
Epoxide hydrolases (mEH, sEH)

32
Q

Phase 2 of drug metabolism involves what types of enzymes? Give examples.

A 
Transferases
Sulfotransferases (SULT)
UDP-glucuronosyltransferases (UGT)
Glutathione-S-transferases (GST)
N-acetyltransferases (NAT)
Methyltransferases (MT)
Lots of addition.
33
Q

Phase 3 of drug metabolism involves which enzymes?

A

Alcohol dehydrogenases
Aldehyde Dehydrogenases
NADPH-quinone oxidoreductase
Lots of reductions.

34
Q

How many genes, families, and subfamilies make up CYPs?

A

~57 genes, 18 families, 43 subfamiliesFamilies 1,2 and 3 are responsible for drug metabolism

35
Q

What explains the differences in drug clearance b/w different drugs that interact with CYPS?

A

Polymorphisms (SNPs).

36
Q

If you have CYP2D6…what does each of these letters/numbers mean?

A

CYP=Cytochrome P450
2-genetic family
D-genetic subfamily
6-specific gene

37
Q

Which CYPS metabolize the most drugs?

A

3a4 is involved in a large number of the drugs that are prescribed. 2D6 & 2C9 & 2C19 are also relevant.

38
Q

What is the first pass effect?

A

This is when a drug is absorbed in the stomach or first part of the SI…it goes into portal circulation & metabolized by the liver before it gets into general circulation. Once it gets to the body, it is at lower levels. Called—first pass effect. Drug levels have already taken this into account.

39
Q

What is the deal with first order elimination?

A 
Most drugs are eliminated by a first-order process. With first-order elimination, the amount of drug eliminated is directly proportional to the serum drug concentration.
At Css (steady state) the amount of drug you administer is equal to the amount of drug that was just excreted. 
Although the amount of drug eliminated in a first-order process changes with concentration, the fraction of a drug eliminated remains constant. The elimination rate constant (Kel) represents the fraction of drug eliminated per unit of time.
40
Q

When is Css especially desirable for drug dosing?

A

For chronic therapy.

41
Q

When the amount of drug exceeds the elimination rate constant…you exhibit what kinds of kinetics?

A

Zero order elimination

42
Q

When does slope=-kel?

A

When you plot an elimination on a log scale. It forms a straight line with a slope of the elimination rate constant.

43
Q

When can you use a one compartment model when thinking about drugs?

A

when the drug distributes rapidly

44
Q

In a two compartment model you have a biphasic line. Describe the significance of this.

A

First part of line represents the distribution of the drug from the central compartment to the peripheral compartment. The second part of the line represents the elimination of the drug from peripheral tissues. This second part has a straight line on a log scale.
**use this when the drug takes a while to distribute.

45
Q

Which of these processes exhibits a constant amount of drug eliminated per unit time? First order, zero order

A

Zero order

**first order has a constant proportion

46
Q

What are some good reasons to closely monitor the drugs given to patients? What are some examples of this specifically?

A

Narrow therapeutic range. Digoxin
Unpredictable dose/response relationship. Phenytoin
Significant consequences from toxicity. Warfarin
Correlation between Css and efficacy or toxicity. Lithium

47
Q

How long does it take to reach a steady state?

A

The time required to reach steady-state is approximately 4 to 5 half-lives.

48
Q

How does the length of infusion affect the peak level of a drug?

A

the longer the period of infusion–the higher the peak.

49
Q

What is creatinine a byproduct of? If it goes up in the body–what problem might you have?

A

a byproduct of muscle metabolism
**could be a renal fcn problem
Note: Creatinine is filtered & excreted, but no secreted or reabsorbed.

50
Q

Creatinine clearance is a good estimate of what?

A

glomerular filtration rate.

51
Q

In kidney disease what happens to filtration, secretion, reabsorption & excretion? What happens to nephron number & fcn?

A

Nephron numbers decrease.
The ones that remain are fully fcnl, however.
Filtration etc all decreases, but remains robust in the nephrons that stick around.

52
Q

If you plot Kel on the y axis & Creatinine Clearance on the x axis…what is the equation for the line?

A

Kel = Knr + (b x CLcr)

53
Q

The y intercept is Knr. What is this?

A

the amount of creatinine that will be eliminated with no renal fcn.

54
Q

Usually using creatinine clearance is a great way to assess renal function. There are a few exceptions. What are they?

A

Liver dysfunction= is associated with over prediction of CLcr. Equations should not be used in patients with liver disease.
Emaciated= have low serum creatinine secondary to decreased muscle mass, resulting in a significant over prediction of CLcr.
Elderly= may have low serum creatinine concentrations secondary to decreased muscle mass, leading to a possible over prediction of CLcr.
Unstable renal function= PK consult correcting for rising serum creatinine, may be more accurate in these patients.
**MOST OF these lead to OVER estimation of clearance.

55
Q

What are the equations for estimating creatinine clearance?

A

CLcr Males = Wt(140 - Age) / (SCr x 72)

CLcr Females = 85% of male value

56
Q

What is the Jeliffe Method for estimating creatinine clearance? This is better in patients with unstable renal fcn.

A

Estimate urinary creatinine excretion rate (E)
E Males = Wt x (29.305 -[0.203 x (age)])
E Females = Wt x (25.3 -[0.18 x (age)])
Correct for rising serum creatinine
E = E - [4 x ABW x (SCr1-SCr2)] / D
SCr1 = the latest serum creatinine; SCr2 = the earlier serum creatinine
D = the number of days between
Calculate corrected creatinine clearance (CLcr)
CLcr = (E * 0.12) / (SCr x BSA)
SCr = most recent serum creatinine

57
Q

What is the minimum inhibitory conc’n?

A

the minimum level of the drug needed to have an effect

58
Q

What does time above MIC tell us?

A

Time-dependent killing and minimal to moderate persistent effects

59
Q

What does the AUC/MIC ratio tell you?

A

Time-dependent killing and prolonged persistent effects

60
Q

What does the peak/MIC ratio tell you?

A

Concentration-dependent killing and prolonged or persistent effects

61
Q

What are some examples of beta lactams?

A 
penicillins
penams
penems
carbapenems
cephalosporins
clavulanic acids
62
Q

Beta lactams exhibit conc’n independent killing. What does this mean? How does this affect dosing strategy?

A

as long as you are above MIC you are killing & it doesn’t matter how high you go-will kill the same amount.
Strategy: maximize exposure time by giving small frequent doses–continuous IV infusion

63
Q

What is the post-antibiotic effect? Do beta lactams exhibit this?

A

. PAE is the persistent suppression of bacterial growth following antibiotic exposure.
Beta lactams don’t have this.

64
Q

Vancomycin, carbapenems, macrolides, and clindamycin have similar features & similar dosing ideals. What are they?

A

intermediate post antibiotic effect-it’s okay if they drop below MIC for a bit.
kill rate is still conc’n independent
Strategy: maximize time above MIC w/ small & frequent doses. Not as much so as beta lactams w/ a continuous IV infusion.

65
Q

When is vancomycin indicated?

A

for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci.

It is indicated for penicillin-allergic patients, for patients who cannot receive or who have failed to respond to other drugs, including the penicillins or cephalosporins, and for infections caused by vancomycin-susceptible organisms that are resistant to otherantimicrobialdrugs.

Block 6; Week 2-Michelle (8 decks)

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